RRC ID 77102
Author Grubb T, Maganti S, Krill-Burger JM, Fraser C, Stransky L, Radivoyevitch T, Sarosiek KA, Vazquez F, Kaelin WG, Chakraborty AA.
Title A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-XL Antiapoptotic Protein in Kidney Cancer.
Journal Clin Cancer Res
Abstract PURPOSE:Advanced/metastatic forms of clear-cell renal cell carcinomas (ccRCC) have limited therapeutic options. Genome-wide genetic screens have identified cellular dependencies in many cancers. Using the Broad Institute/Novartis combined short hairpin RNA (shRNA) dataset, and cross-validation with the CRISPR/Cas9 DepMap (21Q3) dataset, we sought therapeutically actionable dependencies in kidney lineage cancers.
EXPERIMENTAL DESIGN:We identified preferential genetic dependencies in kidney cancer cells versus other lineages. BCL2L1, which encodes the BCL-XL antiapoptotic protein, scored as the top actionable dependency. We validated this finding using genetic and pharmacologic tools in a panel of ccRCC cell lines. Select BCL-XL-dependent (versus independent) cell lines were then transcriptionally profiled to identify biomarkers and mechanistic drivers of BCL-XL dependence. Cell-based studies (in vitro and in vivo) and clinical validations were used to address physiologic relevance.
RESULTS:Inactivation of BCL-XL, but not BCL-2, led to fitness defects in renal cancer cells, and sensitized them to chemotherapeutics. Transcriptomic profiling identified a "BCL-XL dependency" signature, including an elevated mesenchymal gene signature. A mesenchymal state was both necessary and sufficient to confer increased BCL-XL dependence. The "BCL-XL dependency" signature was observed in approximately 30% of human ccRCCs, which were also associated with worse clinical outcomes. Finally, an orally bioavailable BCL-XL inhibitor, A-1331852, showed antitumor efficacy in vivo.
CONCLUSIONS:Our studies uncovered an unexpected link between cell state and BCL-XL dependence in ccRCC. Therapeutic agents that specifically target BCL-XL are available. Our work justifies testing the utility of BCL-XL blockade to target, likely, a clinically aggressive subset of human kidney cancers. See related commentary by Wang et al., p. 4600.
Volume 28(21)
Pages 4689-4701
Published 2022-11-1
DOI 10.1158/1078-0432.CCR-22-0669
PII 706745
PMID 35776130
PMC PMC9633392
MeSH Apoptosis / genetics Carcinoma, Renal Cell* / drug therapy Carcinoma, Renal Cell* / genetics Cell Line, Tumor Humans Kidney Neoplasms* / drug therapy Kidney Neoplasms* / genetics Proto-Oncogene Proteins c-bcl-2 / genetics Proto-Oncogene Proteins c-bcl-2 / metabolism RNA, Small Interfering bcl-X Protein / genetics bcl-X Protein / metabolism
IF 10.107
Human and Animal Cells OS-RC-2(RCB0753) TUHR4TKB(RCB1198) TUHR10TKB(RCB1275)